tbuckley/cabot-search huggingface dataset:
Sustained potentiation of bystander killing via PTEN-loss driven macropinocytosis targeted peptide-drug conjugate therapy in metastatic triple-negative breast cancer
Authors: Young Seok Cho, Ha Rin Kim, Seong Jin Park, Seung Woo Chung, Yoon Gun Ko, Joo Hye Yeo, Jinu Lee, Sang Kyoon Kim, Jeong Uk Choi, Sang Yoon Kim, Youngro Byun
Journal: Biomaterials (2022)

While conventional approaches for PTEN-loss cancers mainly focus on turning off growth promoting process through modulation of PI3K/AKT pathways, no effective therapeutic treatments that target PTEN-loss cancer cells have yielded results. Moreover, conventional targeted therapies, which are potent against only a subset of cancer cells with limited specificity, bring on temporary response. Here, we report the development of albumin-binding caspase-3 cleavable peptide-drug conjugate (PDC), which utilizes the enhanced albumin metabolism pathway in PTEN-loss cancer cells to enhance the intracellular delivery of chemotherapeutic payload that could exert a bystander killing effect. Albumin metabolism-mediated apoptosis triggered expression of caspase-3 allows the continuous activation of the PDC, accumulation of payloads, sustained upregulation of tumoral caspase-3, and intensified in-situ apoptosis. Importantly, PDC strategy exerts potent therapeutic efficacy against PTEN-loss metastatic triple-negative breast cancer, the highly aggressive and heterogenous nature of which remains a challenge conventional targeted therapies need to overcome. This study thus presents a conceptually novel approach to treat PTEN-loss cancer and creates new translational perspectives of exploiting PTEN-loss for providing an avenue to advance current targeted therapy.
Safety and efficacy of abacavir for treating infants, children, and adolescents living with HIV: a systematic review and meta-analysis
Authors: Julie Jesson, Laura Saint-Lary, Marc Harris Dassi Tchoupa Revegue, John O’Rourke, Claire L Townsend, Françoise Renaud, Martina Penazzato, Valériane Leroy
Journal: The Lancet Child & Adolescent Health (2022)
Advances in nanomaterials for the diagnosis and treatment of head and neck cancers: A review
Authors: Cheng Yu, Long Li, Shiwen Wang, Yuanhang Xu, Lu Wang, Yongbiao Huang, Ahmed Hieawy, He Liu, Jingzhi Ma
Journal: Bioactive Materials (2022)

Nanomaterials (NMs) have increasingly been used for the diagnosis and treatment of head and neck cancers (HNCs) over the past decade. HNCs can easily infiltrate surrounding tissues and form distant metastases, meaning that most patients with HNC are diagnosed at an advanced stage and often have a poor prognosis. Since NMs can be used to deliver various agents, including imaging agents, drugs, genes, vaccines, radiosensitisers, and photosensitisers, they play a crucial role in the development of novel technologies for the diagnosis and treatment of HNCs. Indeed, NMs have been reported to enhance delivery efficiency and improve the prognosis of patients with HNC by allowing targeted delivery, controlled release, responses to stimuli, and the delivery of multiple agents. In this review, we consider recent advances in NMs that could be used to improve the diagnosis, treatment, and prognosis of patients with HNC and the potential for future research.
Transparent Polyurethane Film as an Intravenous Catheter Dressing
Authors: Karen K. Hoffmann
Journal: JAMA (1992)

<h3>Objective.</h3> —To obtain a quantitative estimate of the impact on infectious complications of using transparent dressings with intravenous catheters. <h3>Data Sources.</h3> —Meta-analysis of all studies published in the English literature, including abstracts, letters, and reports that examined the primary research question of infection risks associated with transparent compared with gauze dressings for use on central and peripheral venous catheters. Studies were identified by use of the MEDLINE database using the indexing terms<i>occlusive dressings, transparent dressings</i>, and<i>infection</i>and by review of referenced bibliographies. <h3>Study Selection.</h3> —Seven of the 15 studies (47%) of central venous catheters and seven of 12 studies (58%) of peripheral catheters met our inclusion criteria for analysis. All studies used a prospective cohort design, utilized hospitalized patients, and reported at least one of our defined outcomes. <h3>Extraction.</h3> —Data for each study were abstracted independently by three investigators. At least three studies were used in the analysis of each outcome. <h3>Data Synthesis.</h3> —Applying a Mantel-Haenszel χ<sup>2</sup>analysis, use of transparent dressings on central venous catheters was significantly associated with an elevated relative risk (RR) of catheter tip infection (RR = 1.78; 95% confidence interval [CI], 1.38 to 2.30). Catheter-related sepsis (RR = 1.69; 95% CI, 0.97 to 2.95) and bacteremia (RR = 1.63; 95% CI, 0.76 to 3.47) were both associated with an elevated RR. Use of transparent dressings on peripheral catheters was associated with an elevated RR of catheter-tip infection (RR=1.53; 95% CI, 1.18 to 1.99) but not phlebitis (RR = 1.02; 95% CI, 0.86 to 1.20), infiltration (RR = 1.12; 95% CI, 0.92 to 1.37), or skin colonization (RR =0.99; 95% CI, 0.90 to 1.09). <h3>Conclusion.</h3> —The results demonstrated a significantly increased risk of catheter-tip infection with the use of transparent compared with gauze dressings when used with either central or peripheral catheters. An increased risk of bacteremia and catheter sepsis associated with the use of transparent compared with gauze dressings for use on central venous catheters was suggested. (<i>JAMA</i>. 1992;267:2072-2076)
Treatment of Mild Hypertension Study
Authors: James D. Neaton
Journal: JAMA (1993)

<h3>Objective.</h3> —To compare six antihypertensive interventions for the treatment of mild hypertension. <h3>Design.</h3> —Randomized, double-blind, placebo-controlled clinical trial. <h3>Setting.</h3> —Four hypertension screening and treatment centers in the United States. <h3>Participants.</h3> —Hypertensive men and women, aged 45 to 69 years, with diastolic blood pressure less than 100 mm Hg. <h3>Intervention.</h3> —Sustained nutritional-hygienic advice to all participants to reduce weight, dietary sodium intake, and alcohol intake, and increase physical activity. Participants were randomly allocated to take (1) placebo (n=234); (2) chlorthalidone (n=136); (3) acebutolol (n=132); (4) doxazosin mesylate (n=134); (5) amlodipine maleate (n=131); or (6) enalapril maleate (n=135). <h3>Main Outcome Measures.</h3> —Blood pressure, quality of life, side effects, blood lipid levels and analysis of other serum components, echocardiographic and electrocardiographic changes, and incidence of cardiovascular events over an average of 4.4 years of follow-up. <h3>Results.</h3> —Blood pressure reductions were sizable in all six groups, and were significantly greater for participants assigned to drug treatment than placebo ( — 15.9 vs — 9.1 mm Hg for systolic blood pressure and — 12.3 vs —8.6 mm Hg for diastolic blood pressure;<i>p</i>&lt;.0001). After 4 years, 59% of participants assigned to placebo and 72% of participants given drug treatment continued on their initial medication as monotherapy. A smaller percentage of participants assigned to the drug-treatment groups died or experienced a major nonfatal cardiovascular event than those assigned to the placebo group (5.1% vs 7.3%;<i>P</i>=.21). After including other clinical events, the percentage of participants affected was 11.1% for those in the drug-treatment groups and 16.2% for those in the placebo group (<i>P</i>=.03). Incidence rates of most resting electrocardiographic abnormalities were lower and quality of life was improved more for those assigned to drug-treatment groups rather than the placebo group. Differences among the five drug treatments did not consistently favor one group in terms of regression of left ventricular mass, blood lipid levels, and other outcome measures. <h3>Conclusions.</h3> —As an initial regimen, drug treatment in combination with nutritional-hygienic intervention was more effective in preventing cardiovascular and other clinical events than was nutritional-hygienic treatment alone. Drug-treatment group differences were minimal. Pending results from large-scale clinical trials to evaluate drug treatments for their effect on cardiovascular clinical events, these findings support the recommendations of the new fifth Joint National Committee report regarding treatment choices for people with stage 1 ("mild") hypertension. (<i>JAMA</i>. 1993;270:713-724)
Covid-19 in the UK: policy on children and schools
Authors: Deepti Gurdasani, Christina Pagel, Martin McKee, Susan Michie, Trish Greenhalgh, Christopher Yates, Gabriel Scally, Hisham Ziauddeen
Journal: BMJ (2022)

Key messages• Pandemic policy on children and schools reflected UK based scientific narratives that did not align with global scientific consensus • Government relied on evidence that downplayed the seriousness of covid-19 in children, underestimated the benefits of precautionary measures, and overestimated the harms of vaccination • Return to school in September 2020 with minimal emphasis on masking and air quality, and inadequate support for isolation may have accelerated community transmission • The public inquiry should explore why the UK was an international outlier in its approach to protecting children and making schools and communities saferChildren in the United Kingdom have been severely affected by the covid-19 pandemic.The closure of schools deprived them of access not only to education but to the many other things that schools provide, from emotional support and life skills to, for some, regular meals.Some schools, especially those attended by children from more affluent families, were able to partially compensate by moving lessons online, but many could not, not least because many of their pupils were in families that were digitally excluded.Children from disadvantaged families were also disproportionately affected by bereavement as many had breadwinners in jobs that placed them at high risk of infection.
Abstract IA16: Trial enrichment and proof of concept studies
Authors: Augusto Villanueva-Rodriguez
Journal: Clinical Cancer Research (2022)

Abstract Identification of oncogene addiction loops has provided new therapeutic targets in oncology. Selective targeting of the ABL-BCR fusion in patients with chronic lymphocytic leukemia using imatinib was a major clinical breakthrough. Similar approaches in other solid tumors led to the approval of additional biomarker-driver molecular therapies (e.g., vemurafenib in BRAF mutated melanoma). Success of this approach was contingent on the identification of biomarkers that could help identify patients most likely to respond to these therapies. This spurred efforts to implement clinical trials able to detect efficacy in specific patient populations, specifically those enriched in the biomarker under evaluation. This has also been applied in hepatocellular carcinoma with mixed results. Approval of ramucirumab in patient with elevated AFP is the first example of successful trial enrichment, while tivantinib is paradigmatic of a negative biomarker enrichment trial. Lack of recurrent druggable mutations makes biomarker-driven clinical trials in HCC more difficult, which underscores the need for predictive biomarkers of immune therapies. Citation Format: Augusto Villanueva-Rodriguez. Trial enrichment and proof of concept studies [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr IA16.
Abstract PO029: Targeting non-canonical Hippo pathway in NRF2-mutant liver cancer
Authors: Viraj Sanghvi, Aleksander Rust, Josef Leibold, Scott Lowe, Agnes Viale, John Chodera, Ronald C. Hendrickson, Elisa de Stanchina, Hans-Guido Wendel
Journal: Clinical Cancer Research (2022)

Abstract NRF2 is an “undruggable” oncogenic transcription factor recurrently mutated in solid tumors such as liver and lung cancers. Our recent study demonstrates that NRF2 acts by coordinating the redox and metabolic stress responses as well as drug resistance programs in liver and other cancers. Developing an NRF2 inhibitor is a major goal of cancer drug discovery. Here, we identify the non-canonical Hippo pathway protein serine/threonine kinase 38 (STK38/NDR1) as a new NRF2 kinase that is a requirement for its stability and function. STK38 directly phosphorylates NRF2 at two sites (S33 and T559), and both sites contribute to full NRF2 activation. Loss of STK38 disables the redox response in NRF2 driven cancers and leads to tumor regression in vivo. Conversely, STK38 can also activate NRF2 and promote de novo liver cancer development in mice. This oncogenic effect is reflected in low frequency (3%) genomic amplifications in human liver cancers. Importantly, inhibition of the upstream STK38-activating mammalian Hippo kinases STK3/4 (MST2/1) by XMU-MP-1 inactivates STK38-NRF2 regulatory axis in vitroand in vivo. More importantly, XMU-MP-1 produces single agent activity against NRF2-driven liver and lung cancers in vivo in primary and patient derived xenograft (PDX)-based mouse models. In addition, we performed an in-silicoscreen and identified TAE-684 as an STK38 inhibitor that was subsequently confirmed to block STK38 activity in an in vitro kinase assay. TAE-684 treatment resulted in significant growth impairment of NRF2-mutant PDXs in vivo but no activity was observed in NRF2 wildtype counterparts. Together, these results uncover a surprising role of Hippo-related kinase STK38 in NRF2 activation and point to a paradoxical vulnerability in NRF2-driven cancers. Citation Format: Viraj Sanghvi, Aleksander Rust, Josef Leibold, Scott Lowe, Agnes Viale, John Chodera, Ronald C. Hendrickson, Elisa de Stanchina, Hans-Guido Wendel. Targeting non-canonical Hippo pathway in NRF2-mutant liver cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr PO029.
Abstract PR05: A novel kinase inhibitor for B-catenin mutant hepatocellular carcinoma
Authors: Alexander Rialdi, Mary Duffy, Alex Scopton, Amaia Lujambio, Arvin Dar, Ernesto Guccione
Journal: Clinical Cancer Research (2022)

Abstract Purpose: We recently developed a chemical strategy for the diversification and disease-specific improvement of tool and FDA-approved kinase inhibitors, and sought to use this strategy for genotype-specific drug discovery in hepatocellular carcinoma (HCC). Experimental Procedures: Primary and murine-derived HCC organoids were used for drug screening. Expansive multiomic (phosphoproteomics, RNAseq, and ChIPseq) and target engagement analyses were used in combination with in vitro rescue and in vivo efficacy experiments. Data Summary: Currently there are few personalized therapeutic approaches for advanced HCC, which is a leading cause of cancer-related deaths worldwide. b-catenin (CTNNB1)-mutated HCC represents 30% of the disease and is a subset of Wnt-driven tumors particularly unresponsive to current therapies. Using focused chemical libraries derived from clinical multi-kinase inhibitor scaffolds, we screened HCC organoids to identify a CTNNB1-mutant selective small molecule that we dub WNTinib. WNTinib retained exquisite selectivity in human and murine models expressing oncogenic b-catenin, including patient samples. Our multidisciplinary approach revealed that WNTinib inhibits KIT/MAPK signaling at multiple nodes. Moreover, we demonstrate that lack of direct engagement on BRAF and p38a/b kinases differentiates WNTinib from existing clinical kinase inhibitors, is necessary to avoid compensatory feedback signaling, and thereby provides a durable and selective transcriptional block of mutant b-catenin and Wnt targets through re-activation of cytoplasmic enhancer of zest homolog 2 (EZH2). Finally, we demonstrate that the unique mechanism of WNTinib provides superior activity compared to clinical therapies in vivo, including in drug-resistant models of mutant b-catenin HCC. Conclusion: Our studies identify a novel inhibitor of the Wnt pathway and uncover a previously unknown mechanism to harness the KIT/MAPK/EZH2 pathway to potently and selectively antagonize CTNNB1-mutant HCC with an unprecedented wide therapeutic index. Our study also provides the rationale to explore WNTinib in proof-of-concept trials with enriched CTNNB1- mutant advanced HCC patients. Citation Format: Alexander Rialdi, Mary Duffy, Alex Scopton, Amaia Lujambio, Arvin Dar, Ernesto Guccione. A novel kinase inhibitor for B-catenin mutant hepatocellular carcinoma [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr PR05.
Abstract PO017: HBV alters YAP regulation in liver cancer by remodeling PP2A complexes
Authors: John Gordan, Adriana Pitea, Rigney E Turnham, Manon Eckhardt, Gwendolyn M Jang, Huat Lim, Alex L Choi, Sourav Bandyopadhyay, Danielle Swaney, Kevan Shokat, Trey Ideker, Nevan Krogan
Journal: Clinical Cancer Research (2022)

Abstract Viral hepatitis promotes hepatocellular carcinoma (HCC) initiation by inducing inflammation, cellular stress and cell death. However, the cell-intrinsic effects of viral infection in advanced HCC remain unclear. We used affinity purification mass spectrometry to develop a complete map of 145 interactions among Hepatitis B Virus (HBV) and host proteins in the HUH7 HCC tumor cell line, identifying known and novel HBV/host protein-protein interactions. We integrated this map with HCC genomes, identifying 61 proteins with preferential mutation in non-HBV HCC, suggesting that their interaction with HBV plays a role in cancer. Focusing on proteins that directly interact with the HBV oncoprotein X (HBx), we found that HBx rewires the effect of the PP2A phosphatase on HCC signaling. HBx binding excluded striatin-family regulatory subunits from the PP2A complex, causing Hippo kinase activation. This effect creates a requirement for integrin signaling to mTOR complex 2 to maintain expression of the YAP oncoprotein, critical for HCC growth. Thus, HBV rewires HCC signaling and may promote targetable dependencies. Citation Format: John Gordan, Adriana Pitea, Rigney E Turnham, Manon Eckhardt, Gwendolyn M Jang, Huat Lim, Alex L Choi, Sourav Bandyopadhyay, Danielle Swaney, Kevan Shokat, Trey Ideker, Nevan Krogan. HBV alters YAP regulation in liver cancer by remodeling PP2A complexes [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr PO017.
Abstract IA04: Metabolic control of HCC initiation and progression
Authors: Michael Karin, Li Gu, Yahui Zhu
Journal: Clinical Cancer Research (2022)

Abstract Non-alcoholic steatohepatitis (NASH) is quickly becoming the leading HCC etiology. NASH can lead to HCC by altering liver metabolism, inducing oncogenic mutations, causing tumor promoting inflammation as well as the immunosuppression of anti-HCC immunity. We have established an accurate model for studying NASH-induced HCC development, the MUP-uPA mouse, and used it to show that elevated TNF production by liver macrophages contributes to both NASH and HCC progression. The major cause of TNF induction during NASH is gut-derived endotoxin, whose infiltration into the portal circulation is enhanced by barrier disrupting diets that are high in fats or fructose. By disrupting autophagy and activating NF-kB, HFD feeding of MUP-uPA mice results in accumulation of p62, the major constituent of Mallory-Denk bodies, within hepatocytes. Accumulation of p62 is not required for induction of hepatosteatosis but it greatly accelerates and enhances NASH to HCC progression through the activation of NRF2 and mTORC1. Conditional activation of NRF2 in hepatocytes results in hepatomegaly due to induction of EGF and PDGF family members as well as altered liver metabolism, in part by triggering the degradation of fructose-1,6 bisphosphate phosphatase (FBP1). FBP1 is rate limiting for gluconeogenesis and its germ-line inherited deficiency results in a complex metabolic disorder that includes hypoglycemia, lactic acidosis, hepatomegaly, hepatosteatosis, hyperlipidemia and liver damage and is manifested only in response to glucose starvation. By generating Fbp1ΔHep mice, we found that FBP1 has enzymatic and non-enzymatic activities, the latter of which are due to formation of a multiprotein complex with aldolase B (ALDOB) and PP2A-C that interacts with AKT, dephosphorylates it and inhibits its activation. By inhibiting AKT activation, FBP1 and ALDOB suppress HCC development. Citation Format: Michael Karin, Li Gu, Yahui Zhu. Metabolic control of HCC initiation and progression [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr IA04.
Abstract PO006: The Role of Obesity-associated Allograft Inflammatory Factor-1 in Liver Cancer Cell Growth
Authors: Jessie Waltenbaugh, Curissa Groll, Kelsie Raign, Ramona Price
Journal: Clinical Cancer Research (2022)

Abstract Introduction: Obesity is a risk factor in the development of liver cancer. The obesogenic tumor microenvironment is of particular importance in liver tumorigenesis due in part to lipid accumulation and monocyte recruitment which differentiate into pro-inflammatory macrophages. A novel macrophage-associated protein, whose role in obesity-associated liver tumorigenesis has yet to be explored, is allograft inflammatory-factor 1 (AIF-1). AIF-1 is a calcium binding inflammation response scaffold protein. Although, proliferation and migration have been studied, https://scholar.google.com/citations?view_op=view_citation&amp;hl=en&amp;user=AAeKZnoAAAAJ&amp;sortby=pubdate&amp;citation_for_view=AAeKZnoAAAAJ:8dzOF9BpDQo Cactivation of kinase pathways, cell survival, cell death, ROS production and lipogenesis have yet to be explored. AIF-1 is upregulated in both liver cancer and obese individuals. Our research objective is to determine the functional role of AIF-1 in promoting physiological processes important for liver tumorigenesis including proliferation, survival, ROS, and lipogenesis, and 2) determine the contribution of Akt and Erk in promoting this in-vitro phenotype. Methods: HepG2 and SNU-449 liver cancer cells were exposed to AIF-1 (10uM) with or without 10 μM ly294002 (PI3K inhibitor), 10 μM PD98059 (MAPK inhibitor), or 5μM NPS-2143 (calcium sensing receptor inhibitor). Cells were assessed for proliferation, ROS production, lipogenesis, cytotoxicity, and cell survival. Immunoblot analysis was used to measure phosphorylated Akt, Erk, IL-6, and NF-kB protein levels. Results: AIF-1 increased proliferation in HepG2 and SNU-449 liver cancer cells. Inhibiting Akt, and Erk signaling decreased AIF-1-induced proliferation while NPS-2143 CaSR inhibitor decreased proliferation only in HepG2 cells. AIF-1 promoted ROS production and the addition of Akt inhibitor blocked AIF-1 ROS production in both cell lines. Significant differences in lipogenesis were not observed among various treatments in HepG2 and SNU-449 cells. AIF-1 increased cell survival, cytotoxicity and phosphorylation of Akt and Erk, when compared to control. Conclusions: Obesity-associated AIF-1 increased proliferation, ROS, and survival while differential effects were observed with Akt or Erk inhibition. Citation Format: Jessie Waltenbaugh, Curissa Groll, Kelsie Raign, Ramona Price. The Role of Obesity-associated Allograft Inflammatory Factor-1 in Liver Cancer Cell Growth [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr PO006.